JP2731032B2 - Detection and treatment methods of malignant and non-malignant lesions by photochemotherapy - Google Patents

Detection and treatment methods of malignant and non-malignant lesions by photochemotherapy

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JP2731032B2
JP2731032B2 JP2510192A JP51019290A JP2731032B2 JP 2731032 B2 JP2731032 B2 JP 2731032B2 JP 2510192 A JP2510192 A JP 2510192A JP 51019290 A JP51019290 A JP 51019290A JP 2731032 B2 JP2731032 B2 JP 2731032B2
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シー. ケネディ,ジェームズ
エイチ. ポッティア,ロイ
エル. レイド,ロバート
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クイーンズ ユニバーシティ アット キングストン
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/555Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation; Therapies using these preparations
    • A61K41/0057Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/00615-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA

Description

【発明の詳細な説明】 発明の分野 それぞれ誘導的蛍光および光化学療法による、或る種の組織異常(癌性および非悪性の両方)の検出および治療に関する。 According DETAILED DESCRIPTION OF THE INVENTION Each inductive fluorescence and photochemotherapy Field of the Invention relates to the detection and treatment of certain tissue abnormalities (both cancerous and non-malignant).

発明の背景 通常は皮膚に影響を及ぼす組織異常は、外観検査と触診の組合せにより検出および評価される。 Background of the Invention typically affect tissue abnormalities in the skin is detected and evaluated by a combination of palpation and visual inspection. 或る臨床的状況では、非白色光(紫外かまたは可視中の狭いバンド) In certain clinical situations, non-white light (narrow band of ultraviolet or in the visible)
の使用により、または希酢酸もしくは或る種の染料といった対比強化剤の事前適用により、外観検査の感度を高めることができる。 Of the use or by pre-application of dilute acetic acid or contrast enhancing agents such as certain types of dyes, it is possible to increase the sensitivity of the visual inspection. 触診できない表面を含む組織異常(例えば気管支または膀胱)は、適当なスコープにより視覚化することができる。 Tissue abnormalities including surfaces that can not be palpated (such as the bronchi or the bladder) may be visualized by a suitable scope. 幾つかの特殊スコープは、誘導蛍光を検出することができる。 Some of the special scope, it is possible to detect the induced fluorescence. 問題の異常が組織の血管形成の範囲またはパターンのいずれかの相違に関連するならば、そのようなスコープを用いて、それを病変組織と近隣の正常組織の両方の血管系に通過させた時に注入された蛍光薬剤を視覚化することにより、異常に関与する領域の限界を決定することができる。 If abnormal problems associated with any differences in the extent or pattern of angiogenesis tissue using such scope, it when passed through the vascular system of both the diseased tissue and the neighboring normal tissue by visualizing the injected fluorescent agent, it is possible to determine the limits of the area to be abnormally involved.

加えて、蛍光検出スコープは、外因性ポルフィリン、 In addition, fluorescence detection scope, exogenous porphyrins,
例えばヘマトポルフィリンIX(Hp IX)、ヘマトポルフィリン誘導体(HpD)または「ジヘマトポルフィリンエーテル」(フォトフリンII)の静注後に強力なポルフィリン蛍光を示す組織の領域を同定するのに実験的に使用されている。 For example hematoporphyrin IX (Hp IX), experimentally used to identify regions of the tissue exhibiting strong porphyrin fluorescence after intravenous injection of hematoporphyrin derivative (HpD), or "di hematoporphyrin ether" (Photofrin II) ing. そのようなポルフィリンは、半優勢的に悪性組織中に蓄積する傾向があるが、それらは損傷後に再生している組織または胚もしくは胎児の迅速に成長している組織にも蓄積する。 Such porphyrins, semi predominantly tend to accumulate in malignant tissue, but they also accumulate in tissues that are rapidly growing tissues or embryos or fetuses are playing after injury. 正常な肝臓、脾臓および腎臓もまた、それらのポルフィリンを蓄積する傾向がある。 Normal liver, spleen and kidney also tend to accumulate these porphyrins. そのような化合物および蛍光検出スコープを使用して、標準形式の外観検査により同定するには小さすぎる悪性組織の領域が気管支および膀胱において同定されている。 Using such compounds and fluorescence detection scope, areas of malignant tissue has been identified in the bronchi and bladder too small to be identified by visual inspection of the standard format.

ポルフィリンが半選択的に蓄積する細胞及び組織を「ポルフィリンが半選択的に蓄積する細胞」と称する。 Cell and tissue porphyrins accumulate semi selectively referred to as "cells porphyrins accumulate semi selective".
このような細胞の性質は、文献、内因性ポルフィリンの静脈内注射の後に強いポルフィリン蛍光を示すもの、又は既知の方法により実験的に決定することができるものとして報告されている。 The nature of such cells can be found in the literature, show a strong porphyrin fluorescence following the intravenous injection of endogenous porphyrins, or have been reported as those which can be determined experimentally by known methods.

不運にも、Hp IX,HpDまたはフォトフリンIIの静注後に少なくとも2週間(場合によっては2ヶ月以上)、臨床的に有意な(光感作)量のポルフィリンが皮膚中に存続する。 Unfortunately, Hp IX, at least 2 weeks after intravenous injection of HpD or Photofrin II (two months or more in some cases), clinically significant (photosensitizing) amount of porphyrin persists in the skin. このことは、患者が注射後の長期間の間、日光(直射または窓ガラスを通った日光)への暴露を避けなければならないことを意味する。 This means that the patient for long periods of time after injection, must avoid exposure to sunlight (sunlight through the direct or glazing). 理解できることだが、 Although it can be understood,
患者の応諾(compliance)がしばしば乏しくなり、そしてポルフィリンの診断または治療的注射後の数週間は偶発的光毒症の「日焼け」が一般に起こる。 Patient compliance (compliance) is often poor, and "tan" in a few weeks after diagnosis or therapeutic injection of porphyrin accidental light poison diseases generally occur. 持続性の光感作がこの方法に関係する主要な危険であり、そしてあまり広範に利用されない理由である。 Sustainability of light sensitization is a major risk associated with this method, and is a reason that is not very widely used.

癌の標準または常用の治療形式は、手術、放射線療法および化学療法である。 Standard or conventional forms of treatment for cancer are surgery, radiation therapy and chemotherapy. しかしながら、光化学療法または光力学療法(PDT)を含む他の治療形式も知られている。 However, it is also known other forms of treatment including photochemotherapy or photodynamic therapy (PDT). PDTは、経験に基づいて、幾つかの異なるタイプの癌並びに乾癬のような或る種の非悪性病変を治療するために現在使われている。 PDT is based on the experience, to treat certain non-malignant lesions such as several different types of cancer and psoriasis are currently used. 患者は、処置すべき組織に対して或る程度の特異性を有する光活性化試薬を投与される。 Patient is administered photoactivatable reagent having a degree of specificity for the tissue to be treated. 次いで標的組織を含む組織領域が、標的組織を破壊するが同じ処置領域中の他の組織に対しては穏和で且つ可逆的な損傷のみを生じるような光活性化光に暴露される。 Tissue region containing the target tissue then is, destroys the target tissue is exposed to light activation light such as occurs only mild in and reversible damage to other tissues in the same treatment area.

現在、臨床用途の2つの主要タイプの光化学療法薬がある。 Currently, there are two of photodynamic therapy drugs of major types of clinical applications. 第一のタイプであるメトキシソラレンは全身投与される。 Methoxypsoralen is the first type is administered systemically. それらを活性化するために紫外光は不可欠である。 Ultraviolet light in order to activate them is essential. 紫外光へのソラレン含有組織の局所的暴露は、該薬剤を生存細胞のDNAに共有結合させ、それらの増殖力を破壊する局所的な光化学反応を誘導する。 Local exposure psoralen-containing tissues to ultraviolet light to covalently bond the agent to the DNA of living cells, induces localized photochemical reaction that destroys their viability. 第二のタイプであるポルフィリンは、全身投与されるが(静注により)、時には局所的にまたは病変内注射のいずれかにより投与されることがある。 Porphyrin is a second type, (intravenously) but is administered systemically, it may be administered at times by either locally or intralesional injection. それらは可視(赤色)光により活性化され得る。 They can be activated by visible (red) light. そのような光へのポルフィリン含有組織の局所的暴露は、細胞成分とポルフィリン分子との間の化学反応を誘導しない。 Such local exposure of the porphyrin-containing tissues to light does not induce a chemical reaction between cell components and the porphyrin molecules. その代わり、ポルフィリンは、光活性化光のエネルギーをトラップし、次いでそれを酸素分子に渡し、これを次に近隣の分子または構造を酸化することのできる励起状態にすることにより、触媒として働く。 Instead, porphyrin traps the energy of photoactivation light, then passes it to the oxygen molecule, by the excited state which can then oxidize nearby molecule or structure which acts as a catalyst. 細胞死は、主としてDNAの損傷により引き起こされるのではなく、本質的膜構造の損傷により引き起こされる。 Cell death is not primarily from being caused by damage to DNA, caused by damage to essential membrane structures.

光化学療法は、現在、或るタイプの癌および乾癬を含む非悪性病変の治療に使われている。 Photodynamic therapy is currently used to treat non-malignant lesions, including certain types of cancer and psoriasis. そのような療法の目標は、時には治療(主に基底細胞癌について)であるが、通常は、標準的な療法形式がおそらく有意な程度の効果を患者に与えるであろうと思われる時には、目標は局所コントロールによる緩和である。 The goal of such therapy is sometimes treatment (mainly for basal cell carcinomas), usually, when you think that would standard therapy form gives perhaps significant degree of effects on the patient, the goal is a relaxation by local control.

メトキシソラレン(PUVA)療法は、主に乾癬の治療に使われるが、皮膚に影響を及ぼすごく表面の癌(主にキノコ状真菌症)を治療するのにも時々使われる。 Methoxypsoralen (PUVA) therapy is used mainly for the treatment of psoriasis, sometimes also used to treat cancer of the extreme surface affects the skin (mainly mushroom mycosis). しかし、そのような治療には2つの深刻な問題点がある。 However, such treatment has two serious problems. 第一は、この方法がヒトにおいて発癌性であると証明されていることである。 The first is that this method has proven to be carcinogenic in humans. 第二は、光活性化光は大部分の組織に非常に強く吸収されるので、悪性組織を殺すことができる深さは、照射表面下の数ミリメートルに限定されることである。 Second, since the light-activated light is absorbed very strongly to most tissues, the depth that can kill malignant tissue is to be limited to a few millimeters below the illuminated surface. それらの問題点は、光化学療法に対するメトキシソラレンの有用性を厳しく制限する。 These problems severely limit the usefulness of methoxypsoralen for photodynamic therapy.

現在、光化学療法に最も一般的に使われているポルフィリンは、ヘマトポルフィリンIX(Hp IX)、ヘマトポルフィリン誘導体(HpD)、およびHpDの半精製形であるフォトフリンII(Photofrin II)である。 Currently, porphyrins are most commonly used in photodynamic therapy are Hematoporphyrin IX (Hp IX), a hematoporphyrin derivative (HpD), and a photo is a semi-purified form of HpD furin II (Photofrin II). ポルフィリンを光感作剤として使用する時、DNAの損傷よりもむしろ本質的膜構造の損傷により細胞死が生じる。 When using porphyrins as photosensitizing agents, cell death caused by injury essentially film structure rather than damage DNA. 従って、悪性の形質転換は深刻な問題とはならない。 Therefore, malignant transformation is not a serious problem. 更に、ポルフィリンを光活性化するのに使われる可視(赤色)光は、 Furthermore, the visible (red) light that is used to light activates the porphyrins,
メトキシソラレンを光活性化するのに使われる紫外光よりもずっと深く組織に貫通するので、ポルフィリン処理組織を殺すことができる深さがかなり大きい。 Because through the methoxypsoralen much deeper tissue than ultraviolet light used to photoactivation, is substantially greater depth can kill porphyrin processing tissue. また、或るタイプのポルフィリンは悪性組織に優勢的に蓄積する有意な傾向を示すので、近隣の正常組織に臨床上有意な損傷を引き起こすことなく悪性組織を破壊することが時々可能である。 Also, certain types of porphyrins exhibits a significant tendency to predominantly accumulate in malignant tissue, it is sometimes possible to destroy malignant tissue without causing clinically significant damage to neighboring normal tissues.

Hp IX,HpDおよびフォトフリンIIの全身適用の主な問題点は、それらの投与後数週間から数ヶ月の間、光感作濃度が皮膚に存続することである。 Hp IX, major problems of systemic application of HpD and Photofrin II is between several weeks to several months following their administration, is that the photosensitizer concentration persists in the skin. 結果として、皮膚中の光感作剤の濃度が無害なレベルに減少するまで患者が日光(直射または窓ガラスを通過したもの)を避けない限り、深刻な偶発的光毒皮膚反応が起こり得る。 As a result, as long as the patient until the concentration of the photosensitizer in the skin is reduced to harmless levels do not avoid sunlight (which has passed through the direct or window glass), may occur serious accidental phototoxic skin reactions. 現在、 Current,
ポルフィリンの投与後の光感作の問題は、注射後少なくとも2週間の間日光への(またはごく明るい人工光への)いかなる形態の暴露も回避し、そしてその後は非常に慎重に日光への暴露を開始するようにアドバイスすることにより、取り扱われている。 Photosensitizers after administration of porphyrins problems, to between injections after at least 2 weeks sunlight (or to very bright artificial light) also avoid exposing any form, and then very carefully exposure to sunlight by advice to start, it is treated. これを実行するのは全く不便であるため、全ての患者がそれらの教示に従うわけではない。 For to do this is quite inconvenient, all patients not follow the teachings. 加えて、高い遮光力を有する日焼け止めの使用は、単に幾らか危険性を減らすだけであり、完全にそれを取り除くわけではないという警告と共に推められる。 In addition, the use of sunscreen with a high light shielding forces are merely remove some risk is advisable with fully warning that reason not get rid of it. 少ないケースでは、処理後1ヶ月以上もの間光感作が存在した患者に、偶発的な光毒障害を防ぐ試みとして数ヶ月間に渡り高い一日量でβ−カロチンが投与された。 The small case, the patient also between photosensitizer more than 1 month after treatment was present in accidental daily dose higher over several months in an attempt to prevent phototoxic failure β- carotene is administered. 最後に、限定された領域に局所的に光感作剤を適用することにより、光毒性を減らす試みが行われている。 Finally, by topical application of photosensitizing agent in the limited area, an attempt to reduce phototoxicity it has been performed.

しかしながら、Hp IXまたはHpDをDMSO(ジメチルスルホキシド)Azone、または組織への拡散を増加させる目的の幾つかの他の賦形剤中において局所適用すると、別の種類の問題に出くわす。 However, when applied topically Hp IX or HpD in DMSO in (dimethylsulphoxide) Azone some other excipients purposes or to increase the diffusion into tissues, come across another type of problem. ポルフィリンがもはや組織に拡散できない(または溶液中に残存する)ような程度までDMSO Azoneが正常組織液により希釈されるようになった後、ポルフィリンはたまたま存在する所で固定化されるようになる傾向がある。 After so porphyrins can no longer diffuse into tissue (or remaining in solution) such extent DMSO Azone is diluted by normal tissue fluids, porphyrin tends to become accidentally immobilized at present is there. 結果として、ポルフィリンの局所適用は悪性組織に対する特異性の低下と関係があり、そして適用部位の近くの正常組織がポルフィリンの局部的濃縮から持続性光感作を発生し得る。 As a result, the topical application of porphyrins is related to the decrease in specificity for malignant tissues, and near normal tissue site of application may occur persistent photosensitization from the local enrichment of porphyrin.

発明の目的 本発明の目的は、誘導的発光による或るタイプの悪性および非悪性組織の検出方法を提供することである。 Purpose The purpose of the present invention the invention is to provide a method for detecting certain types of malignant and non-malignant tissues by inducing luminescence.

本発明の別の目的は、それ自体は光感作剤でないが生体内でプロトポルフィリンIX(Pp IX)の合成を誘導する薬剤を使って全身的または局所的のいずれでも投与することができる光力学(光感作)治療方法を提供することである。 Another object of the present invention, the light may be administered per se either but not photosensitizer with an agent that induces the synthesis of protoporphyrin IX (Pp IX) systemic or local in vivo to provide a mechanical (photosensitization) treatment methods.

発明の記載 本発明の一つの観点によれば、患者の悪性および非悪性病変の検出方法であって、前記病変においてプロトポルフィリンIXの蓄積を誘導するように、ヘムの生合成経路中のプロトポルフィンIXの前駆体の有効量を前記患者に投与し、そして前記プロトポルフィリンIXの吸光スペクトル内の波長を有する光に前記病変を暴露し、それによって前記病変において蛍光を誘導することを含んで成る方法を提供することである。 According to one aspect of the claimed present invention, there is provided a method of detecting a malignant and non-malignant lesions of patients, protoporphyrin said to induce the accumulation of protoporphyrin IX in the lesion, the biosynthetic pathway of heme how administering an effective amount of a precursor of IX to the patient, and the exposing the lesion to light having a wavelength within the absorption spectrum of protoporphyrin IX, thereby comprising inducing fluorescence in the lesion it is to provide a.

本発明の別の観点によれば、患者の皮膚、粘膜、子宮内膜および尿路細胞層(urothelium)の悪性および非悪性増殖過剰病変の処置方法であって、前記病変においてプロトポルフィリンIXの合成を誘導するように、ヘムの生合成経路中のプロトポルフィリンIXの前駆体の有効量を前記患者に投与し、そして前記Pp IXの光活性化作用スペクトル内の波長を有する光に前記病変を暴露し、それによって前記病変中に蛍光を誘導することを含んで成る方法を提供することである。 According to another aspect of the present invention, the patient's skin, mucous membranes, a method of treating malignant and non-malignant hyperproliferative lesions of the endometrium and urinary tract cell layer (urothelium), the synthesis of protoporphyrin IX in the lesion to induce an effective amount of a precursor of protoporphyrin IX in a biosynthetic pathway of heme administering to the patient, and exposing the lesion to light having a wavelength of the light activating effect in the spectrum of the Pp IX and is thereby providing a method comprising inducing fluorescence in said lesion.

本発明の好ましい態様において、好ましいプロトポルフィリンIXの前駆体は、5−アミノレブリン酸として知られる5−アミノ−4−オキソペンタン酸であり、そして光活性化光の好ましい波長は、350−635nmの領域、より好ましくは約635nmの赤色光である。 In a preferred embodiment of the present invention, the precursor of the preferred protoporphyrin IX is 5-amino-4-oxopentanoic acid known as 5-aminolevulinic acid, and a preferred wavelength of the light-activated light region of 350-635nm , more preferably red light of approximately 635 nm.

好ましい態様の詳細な記載 天然に存在する光感作剤であるプロトポルフィリンIX A photosensitizing agent present in the detailed description natural preferred embodiment protoporphyrin IX
(Pp IX)は、ヘム生合成経路におけるヘムの直前前駆体である。 (Pp IX) is immediately before the precursor of heme in the heme biosynthetic pathway. ヘムは種々の重要なヘム含有酵素の合成に必要であるので、全ての有核細胞は少なくともPp IXを合成する最小限の能力を有する。 Since heme is necessary for the synthesis of various essential heme-containing enzymes, all nucleated cells have minimal capacity to synthesize least Pp IX. 或るタイプの細胞および組織は、比較的多量のPp IXを合成することができる。 Certain types of cells and tissues can be relatively synthesize large amounts of Pp IX.
正常条件下では、そのような組織におけるPp IXの合成は、細胞がヘムの要求にかなうのにちょうど十分である速度でPp IXを生産するような厳格なフィードバック制御下にある。 Under normal conditions, the synthesis of Pp IX in such tissue is in strict feedback control under such cells produce Pp IX at a rate which is just sufficient to meet the requirements of the heme. しかしながら、この過程の通常の律速段階である5−アミノレブリン酸(ALA)の合成は、外因性A However, synthesis is a normal rate-limiting step in the process 5-aminolevulinic acid (ALA), the exogenous A
LA、ポルホビリノーゲンまたは他のPp IX前駆体の供給により迂回することができる。 LA, can be bypassed by the supply of porphobilinogen, or other Pp IX precursor. 或る種の組織および器官は、それらが蛍光性で且つ光感作性になるほど大過剰の Certain tissues and organs, a large excess of the more they become and photosensitizer with a fluorescent
Pp IXを蓄積するだろう。 It will accumulate Pp IX. 少なくとも皮膚の場合、Pp IX If at least of the skin, Pp IX
はその場で合成されるように見える。 It looks like is synthesized in situ. Sigma Chemical C Sigma Chemical C
ompanyから市販されておりそして水溶性であるALAは、 The ALA is provided and a water-soluble, commercially available from ompany,
経口、局所または注射により投与することができる。 Oral, it may be administered by local or by injection. 経口または非経口経路は、体の至る所の或る種の良性および悪性組織中への臨床上有用な濃度のPp IXの誘導をもたらす。 Oral or parenteral routes, results in the induction of clinically useful concentrations of Pp IX to certain types of benign and malignant tissues in throughout the body. 或るタイプの組織のみが、過剰のALAを供給した時に臨床上有用な量のPp IXを合成できるので、影響を受けた組織が光活性化光が到達できる部位にある場合にのみ、ALAの供給が有利である。 Only certain types of tissue, it is possible to synthesize Pp IX of clinically useful amounts when fed excess ALA, the affected tissue only if photoactivated light is a site that can be reached, the ALA supply is advantageous. 現時点では、皮膚、 At the moment, the skin,
粘膜(呼吸器、消化器および膣の)、子宮内膜および尿路細胞層(urothelium)の基底細胞癌、基底有棘細胞癌および有棘細胞癌並びに他の病変の処置が期待される。 Mucosa (respiratory, digestive and vaginal), basal cell carcinoma of the endometrium and urinary tract cell layer (Urothelium), treatment of basal squamous cell carcinoma and squamous cell carcinoma, as well as other lesions are expected.
部位としては、(i)皮膚および結膜;(ii)口、咽頭、食道、胃、腸および腸付属器、直腸並びに肛門管の内層;(iii)鼻道、鼻腔、鼻咽頭、気管、気管支および細気管支の内層;(iv)尿管、膀胱および尿道の内層;(v)膣、子宮頚および子宮の内層;(vi)壁側胸膜および肺胸膜;(vii)腹腔および骨盤腔の内層、並びにそれらの腔の内部に含まれる器官の表面;(viii) The site, (i) skin and conjunctiva; (ii) the mouth, pharynx, esophagus, stomach, intestines and intestinal appendages, the lining of the rectum and anal canal; (iii) the nasal passages, nasal cavity, nasopharynx, trachea, bronchi and lining bronchioles; (iv) urinary tract, bladder and urethra inner layer; (v) vaginal, lining of the cervix and uterus; (vi) the parietal pleura and lung pleura; (vii) the lining of the abdominal and pelvic cavity, and the surface of the organ contained within their lumen; (viii)
硬膜および髄膜;(ix)直接的に、手術時に、または針を通して挿入した光ファイバーにより、光活性化光に対してアクセシビリティにされ得る固体組織中の任意の腫瘍、に関わる病変が挙げられる。 Dura and meninges; to (ix) directly, at the time of surgery, or inserted optical fiber through the needle, any tumor of solid tissue which may be the accessibility to light activation light, lesions involving the like.

入射赤色光(600−700nm)の1〜10%が厚さ1cmのヒト組織スラブを通過できる一方、青色光(約400nm)はわずか0.001%かそこらが同じ厚さのヒト組織を通過できることが示されているので、光活性化光の波長は幾らか重要である。 While that can pass through the 1-10% of the thickness 1cm human tissue slab of the incident red light (600-700nm), blue light (about 400 nm) is that only 0.001% or so can pass through human tissue of the same thickness shown since the wavelength of the light-activated light is somewhat important. 従って、光感作剤が強力に赤色光を吸収するならば、より好結果となるであろう。 Therefore, if the photosensitizing agent is strongly absorb red light, it will be more successful. Pp IXは赤色光を強力に吸収する。 Pp IX is strongly absorb red light. 本アプローチは、従来技術を上回る幾つかの利点を有する。 This approach has several advantages over the prior art. 第一に、Pp IXは、正常組織においてHp IX,HpDまたはフォトフリンIIよりもずっと短い半減期を有する。 First, Pp IX has a much shorter half-life than Hp IX, HpD or Photofrin II in normal tissues. これは処置後における偶発的光毒性皮膚反応の危険を大きく減らす。 This greatly reduces the risk of accidental phototoxic skin reactions after treatment. 第二に、或るタイプの病変へのALAの局所適用は、それらの病変内部でPp IX Secondly, topical application ALA to certain types of lesions, Pp IX in their lesions inside
を誘導することができるが、その他の場所では誘導しない。 Although it is possible to induce, not induced in other places. このことは、処置の特異性を改善し、偶発的な光毒性反応をごく低レベルに減らし、そして均一有効量のAL This improves the specificity of the treatment, reducing accidental phototoxic reactions very low, and a uniform effective amount AL
Aを全身的に投与しようとしたならば全身が暴露されたであろうALAとPp IXの両方の量を大きく減少させる。 A The greatly reduces the amount of both will try ALA and Pp IX which is systemically is exposed if you try administered systemically. AL AL
AとPp IXは両方とも普通の代謝産物であり、そして体内の生化学的機構により非常に容易に処理される。 A and Pp IX are both common metabolites, and is very easily handled by the body of the biochemical mechanisms. しかしながら、非常に多量のALAは(多量のHp IXまたはHpDと同様に)、運動神経伝達速度の一時的減少と関係があるので、ALAの用量をまだ有効である最小量に減らすことが望ましい。 However, (as with large amounts of Hp IX or HpD) very high amounts of ALA, since the temporary reduction of motor nerve conduction velocity are related, it is desirable to reduce the minimum amount is still effective dose of ALA. 局所適用は、全身投与よりもずっと少ない Topical application, much less than the systemic administration
ALAを要求する。 To request the ALA. 第三に、Pp IXは光活性化光により迅速に不活性化される。 Thirdly, Pp IX is rapidly inactivated by photoactivation light. 治療線量の光活性化光へのPp IX含有組織の暴露後、処置容量内部の組織の光感作の実質的減少がある。 After exposure of Pp IX-containing tissue into photoactivation light therapy dose, there is a substantial decrease in photosensitization of the treated volume inside the tissue. その結果、特定の病変へのALAの局所適用によりPp IXが誘導されれば、深刻な光毒症の危険なしに処置後すぐに患者を太陽に暴露することができる。 As a result, if Pp IX is induced by topical application of ALA to specific lesions, it may be exposed to the patient after treatment immediately without serious phototoxic diseases dangerous to the sun. 第四に、経口、局所または注射により投与すると、ALAはP Fourth, oral, administration by topical or injection, ALA is P
p IXの効果的な誘導物質である。 It is an effective inducer of p IX. 対照的に、Hp IX,HpD In contrast to, Hp IX, HpD
およびフォトフリンIIは、ほとんどの場合、注射により投与した時のみ効果的である。 And Photofrin II are most often seen effective when administered by injection. このALAの多能性は、医者達による日常使用への近づきやすさを増大させる。 Pluripotent of this ALA increases the accessibility of the day-to-day use by doctors. というのは、経口および局所の投与経路は、非経口よりもずっと便利だからである。 This is because, the route of administration of oral and topical, is because it is much more convenient than the parenteral. 第五に、ALAの投与により光感作され得る正常および異常組織は、Hp IX,HpDまたはフォトフリンIIの投与により光感作され得るものと幾らか異なる。 Fifth, the normal and abnormal tissues can be photosensitising administration of ALA are somewhat different from those that may be photosensitizer administration of Hp IX, HpD or Photofrin II. 従って、ALAは、他の光換作剤が有用でない臨床的状況において有用となり得る。 Therefore, ALA is other light 換作 agents may be useful in clinical settings not useful.

本発明の技術は、既に実施できるものを実施する別の方法であるだけでなく、実際、治療能力の有意な進歩である。 Technique of the present invention, not only a different way of carrying out the those already be implemented, in fact, a significant advance in therapeutic potential.

実施例1 右頬と下顎骨の再発性上皮内有棘細胞癌を有すると診断された87才の患者を、病変あたり、100mgのALAの投与量で17%(w/w)Glaxal基剤中のALAの局所適用により処置した。 87-year-old patient diagnosed as having recurrent intraepithelial squamous cell carcinoma of Example 1 right cheek and mandible, per lesion, 17% at a dose of ALA of 100mg (w / w) Glaxal base in of it was treated by topical application of ALA. 適用の2.5時間後、病変を光活性化光、即ち赤外(熱フィルター)および600nm以下の波長(Hoya R−6 After application of the 2.5 hours, the lesion photoactivation light, namely an infrared (heat filter) and 600nm wavelengths below (Hoya R-6
0フィルター)を除去するために濾過された500ワットのタングステンランプの出力の光に、52.5mW時/cm 2の線量(強度×時間)において暴露した。 0 filter) to the light output 500 watt tungsten lamp that has been filtered to remove, and exposed at a dose of 52.5mW at / cm 2 (intensity × time). 処置後40日間患者を評価し、病変が完全に応答を示したと判断された。 Evaluated 40 days the patient after treatment, lesion is determined to show the complete response.

実施例2 右耳の上部後方および外側に、上皮内有棘細胞癌を有すると診断された73才の患者を、病変あたり35mgの投与量において10%(w/w)Glaxal基剤中のALAの局所適用により処置した。 The upper rear and outside of Example 2 the right ear, the 73-year-old patient diagnosed with intraepithelial squamous cell carcinoma, 10% at a dose of lesions per 35mg (w / w) Glaxal ALA in base They were treated by topical application of. ALAの適用の3時間後、病変を実施例1 3 hours after ALA application, the exemplary lesion Example 1
に記載の光源からの26mW時/cm 2の光活性化光に暴露した。 It was exposed to light activation light of 26mW at / cm 2 from a light source according to. 処置後21日間の評価は、完全な応答を示した。 Evaluation of 21 days after treatment showed a complete response.

実施例3 次の部位に多発性有棘細胞癌を有すると診断された64 64 diagnosed with multifocal squamous cell carcinoma in Example 3 the following sites
才の患者: (1) 背、左肩 (2) 背、右胸郭 (3) 背、右胸郭下方 (4) 左手背側面、指の近く (5) 左手背側面、中央部 (6) 左手、母指関節付近(約10mm隆起) の病変1,2および3を、20%w/w Glaxal基剤中病変あたり20mgのALAで処置した。 Old patient: (1) back, the left shoulder (2) back, right rib cage (3) back, right thorax downward (4) left dorsal surface, close to the finger (5) left dorsal side, the central portion (6) left, the mother lesions 1, 2 and 3 in the vicinity of finger joints (approximately 10mm raised) were treated with ALA of 20% w / w Glaxal base lesions per 20 mg. 3時間後、50mW時/cm 2の線量において実施例1に記載の光源からの光活性化光に暴露した。 After 3 hours, it was exposed to light activation light from a light source described in Example 1 at a dose of 50mW at / cm 2. 処置の10日後、病変1はほとんど完全な応答を有し、病変2は部分的な応答、そして病変3は完全な応答を有した。 After 10 days of treatment, the lesion 1 has almost complete response, lesion 2 partial response and lesions 3 had a complete response. 次いで、病変1および2並びに病変4,5および6を10%w/w Glaxal基剤中の22mgのALAで3時間処置し、そして下記の線量: 病変1−17mW時/cm 2病変2−17mW時/cm 2病変4−26mW時/cm 2病変5−26mW時/cm 2病変6−26mW時/cm 2において、上述の光活性化光に暴露した。 Then, the lesion 1 and 2 and lesion 4, 5 and 6 were treated for 3 hours at 10% w / w Glaxal of 22mg in base ALA, and the following dose: diseased 1-17mW at / cm 2 lesion 2-17mW in time / cm 2 lesion 4-26mW at / cm 2 lesion 5-26mW at / cm 2 lesion 6-26mW at / cm 2, it was exposed to the above-described light-activated light. 処置後25日間、患者は次のように評価された: 病変1−完全な応答 病変2−完全な応答 病変4−再発なし 病変5−部分的応答 病変6−10mmの隆起の約3mmの低下。 25 days after treatment, the patient was evaluated as follows: reduction of the lesion 1 complete response lesions 2- complete response lesion 4 to about 3mm raised without recurrent disease 5 partial response lesions 6-10 mM.

実施例4 43才の患者は、(1)背、左肩および(2)背、高腰椎領域、右側の基底細胞癌を有すると診断され、この患者を33%w/w Glaxal基剤中病変あたり50mgのALAで3時間処置した。 Patients of Example 4 43 years old, (1) the back, the left shoulder and (2) back, high lumbar region, is diagnosed as having basal cell carcinoma of the right, the patient 33% w / w Glaxal base in per lesion for 3 hours, treated with 50mg of ALA. 次いで実施例1に記載の光源から37mW時/c Then 37mW when / c from the light source described in Example 1
m 2において病変を光活性化した。 Lesions were photoactivated in m 2. 処置後64日間の評価は両病変の完全な応答を示した。 Evaluation of 64 days after treatment showed complete response in both lesions.

実施例5 ALAを等張塩溶液に溶かし、次いで皮下または腹腔内注射のいずれかにより、体重1kgあたり100〜500mgの用量においてマウスに全身投与した。 Dissolved Example 5 ALA at equal isotonic salt solution, followed by either subcutaneous or intraperitoneal injections were administered systemically to mice at a dose of 100~500mg per body weight 1 kg. 3時間後、マウスを犠牲にし、子宮の凍結切片を取った。 After 3 hours, the mice were sacrificed, took the frozen sections of the uterus. それらの切片を蛍光顕微鏡により調べると、子宮内膜は強いプロトポルフィリン蛍光を示したが、下層の子宮筋層は示さなかった。 If those sections examined by fluorescence microscopy, although endometrium showed strong protoporphyrin fluorescence, lower myometrium was shown. ALAを全身的に投与したので、それわ確実に子宮筋層中に存在していたにちがいなく、そして子宮筋層におけるプロトポルフィリン蛍光のその後の欠失は、過剰の外因性ALAを供給した時のことを示すにちがいない。 Since the administration of ALA systemically time, it'll no difference to ensure was present myometrium during, and subsequent deletion of protoporphyrin fluorescence in myometrium, which supplies the excess of exogenous ALA it must show that of. 従って、ALAを子宮内膜の表面に直接適用する場合、子宮筋層は光感作性にならないであろうし、そして光活性化光への子宮内膜と子宮筋層のその後の暴露は子宮内膜組織の優先的切除をもたらすであろう。 Therefore, when applied directly to ALA on the surface of the endometrium, myometrium WOULD NOT become photosensitizing, and subsequent exposure of the endometrium and the myometrium to the photoactivation light utero It will result in the preferential ablation of membrane tissue.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl. 6識別記号 庁内整理番号 FI 技術表示箇所 A61N 5/06 A61N 5/06 E (72)発明者 レイド,ロバート エル. カナダ国,オンタリオ ケー7エル 4 ブイ1,キングストン,アール. ────────────────────────────────────────────────── ─── of the front page continued (51) Int.Cl. 6 identification symbol Agency Docket No. FI technology display location A61N 5/06 A61N 5/06 E (72) inventor raid, Robert El., Canada, Ontario cable 7 El 4 buoy 1, Kingston, Earl. アー ル. R. #1,コンコード 5 (56)参考文献 Br. # 1, Concord 5 (56) references Br. J. J. Cancer,Vol. Cancer, Vol. 56 No. 56 No. 5(1987) P. 5 (1987) P. 589−595 Cancer lett. 589-595 Cancer lett. (Shan non,Irel.),Vol. (Shan non, Irel.), Vol. 36 N o. 36 N o. 1(1987)P. 1 (1987) P. 1−10 1-10

Claims (5)

    (57)【特許請求の範囲】 (57) [the claims]
  1. 【請求項1】プロトポルフィリンIXをその代謝前駆体から選択的に蓄積する急速に成長する組織の検出又は処理における患者の生体内での使用のため光化学的療法用又は診断用組成物であって、前記急速に成長する組織は、 1. A photochemically therapeutic or diagnostic composition for use in vivo of a patient in the detection or treatment of rapidly growing tissues selectively accumulate protoporphyrin IX from metabolic precursor thereof , the fast-growing organization,
    皮膚、結膜、粘膜、子宮内膜及び尿路上皮の悪性及び非悪性異常又は病変から成る群から選択されるものであり、該組成は、前記患者の前記組織において光化学的に有効な療法的又は診断的量の前記プロトポルフィリンIX Skin, conjunctiva, mucous membranes, are those selected from the group consisting of malignant and non-malignant abnormalities or lesions endometrium and the urothelium, the composition is photochemically effective therapy or in the tissue of the patient the protoporphyrin IX of diagnostic amount
    が生体内蓄積するのに有効な量の該プロトポルフィリン The amount of the protoporphyrin but effective to bioaccumulate
    IXの前記前駆体を含んで成る、ことを特徴とする組成物。 Wherein comprising the precursor composition, wherein the the IX.
  2. 【請求項2】前記組成物が、光活性化光への前記患者の組織の暴露に先立って該患者に投与される、請求項1に記載の組成物。 Wherein said composition, prior to exposure of the patient's tissue to the light-activated light is administered to the patient, composition according to claim 1.
  3. 【請求項3】前記光活性化光が350〜635ナノメーターの範囲にある、請求項2に記載の組成物。 Wherein the light-activated light is in the range of 350 to 635 nanometers, The composition of claim 2.
  4. 【請求項4】生体内処理されるべき前記患者からの前記急速に成長する組織が、呼吸器、消化器もしくは腔の粘膜、口、咽頭、食道、胃、腸、腸付属器、直腸、肛門管、鼻道、鼻腔、鼻咽腔、気管、気管支、細気管支、尿管、膀胱、尿道、膣、頚管、子宮、壁側胸膜又は肺胸膜、腹腔および骨盤腔の内層、並びにそれらの腔の内部に含まれる器管の表面、硬膜および髄膜の悪性又は良性の異常又は病変から選択される、請求項1に記載の組成物。 Wherein said rapidly growing tissue from the patient to be treated in vivo, respiratory mucosa of the digestive or cavity, mouth, pharynx, esophagus, stomach, intestine, bowel appendages, rectum, anus tubes, nasal passages, nasal cavity, nasopharynx, trachea, bronchi, bronchioles, ureter, bladder, urethra, vagina, cervix, uterus, inner layer of the parietal pleura or lung pleura, abdominal and pelvic cavity, as well as their lumen the surface of the organ contained within, it is selected from the abnormality or lesion of malignant or benign dura and meninges composition of claim 1.
  5. 【請求項5】前記プロトポルフィリンIXの前駆体が5− 5. The precursor of the protoporphyrin IX is 5
    アミノレブリン酸である、請求項1〜4のいずれか1項に記載の組成物。 It is aminolevulinic acid composition according to any one of claims 1 to 4.
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Publication number Priority date Publication date Assignee Title
WO2009130893A1 (en) 2008-04-22 2009-10-29 Sbiアラプロモ株式会社 Method of detecting bladder cancer
WO2010050179A1 (en) 2008-10-27 2010-05-06 Sbiアラプロモ株式会社 Prophylactic/ameliorating agent for adult diseases comprising 5-aminolevulinic acid, derivative of 5-aminolevulinic acid, or salt of 5-aminolevulinic acid or the derivative of 5-aminolevulinic acid as active ingredient
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WO2011145343A1 (en) 2010-05-19 2011-11-24 Sbiアラプロモ株式会社 Antimalarial drug which contains 5-aminolevulinic acid or derivative thereof as active ingredient
WO2012172821A1 (en) 2011-06-16 2012-12-20 Sbiファーマ株式会社 Therapeutic agent for allergic rhinitis
WO2013024589A1 (en) 2011-08-12 2013-02-21 Sbiファーマ株式会社 Prophylactic agent and/or therapeutic agent for sepsis
WO2014092051A1 (en) 2012-12-11 2014-06-19 国立大学法人熊本大学 Nuclear magnetic resonance diagnostic agent, and method for detecting or diagnosing state of cell, tissue or organ in subject using same

Families Citing this family (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6710066B2 (en) * 1989-07-28 2004-03-23 Queen's University At Kingston Photochemotherapeutic method using 5-aminolevulinic acid and other precursors of endogenous porphyrins
US5955490A (en) * 1989-07-28 1999-09-21 Queen's University At Kingston Photochemotherapeutic method using 5-aminolevulinic acid and other precursors of endogenous porphyrins
US5234940A (en) * 1989-07-28 1993-08-10 Queen's University Photochemotherapeutic method using 5-aminolevulinic acid and precursors thereof
US5422093A (en) * 1989-07-28 1995-06-06 Queen's University Photochemotherapeutic method using 5-aminolevulinic acid and precursors thereof
US20040110819A1 (en) * 1991-10-28 2004-06-10 Queen's University At Kingston Photochemotherapeutic method using 5-aminolevulinic acid and other precursors of endogenous porphyrins
EP0831909B1 (en) * 1995-06-05 2005-01-26 Queen's University at Kingston Use of a protoporphyrin ix precursor in the treatment of dermatophytoses and malaria after photoactivation of said protoporphyrin
US20020058008A1 (en) * 1989-07-28 2002-05-16 Kennedy James C. Photochemotherapeutic method using 5-aminolevulinic acid and other precursors of endogenous porphyrins
US6671540B1 (en) * 1990-08-10 2003-12-30 Daryl W. Hochman Methods and systems for detecting abnormal tissue using spectroscopic techniques
US5219878A (en) * 1990-10-05 1993-06-15 Queen's University Tetrapyrrole hydroxyalkylamide photochemotherapeutic agents
US5587394A (en) * 1991-03-28 1996-12-24 The University Of Toledo Production and use of diels alder adducts of vinyl porphyrins, of metal complexes thereof, and of compositions containing such adducts and complexes
SE9103837L (en) * 1991-12-21 1993-06-22 Jonas Johansson Fluorescence diagnosis of cancer using delta-aminolevulinic acid
DE4228106A1 (en) * 1992-08-24 1994-03-03 Medac Klinische Spezialpraep Tumour diagnosis and treatment in organs, esp. urinary system - comprises admin. of gamma-amino-levulinic acid as photosensitiser, detection, and treatment by irradiation with neodymium-yttrium-aluminium-garnet laser
US5368841A (en) * 1993-02-11 1994-11-29 The General Hospital Corporation Photodynamic therapy for the destruction of the synovium in the treatment of rheumatoid arthritis and the inflammatory arthritides
DE4320871C2 (en) * 1993-06-24 1995-05-04 Beiersdorf Ag Cosmetic and dermatological preparations containing delta-aminolevulinic acid
GB9318841D0 (en) * 1993-09-10 1993-10-27 Res Foundation Of The Norwegia Composition
US5441531A (en) * 1993-10-18 1995-08-15 Dusa Pharmaceuticals Inc. Illuminator and methods for photodynamic therapy
US5489279A (en) * 1994-03-21 1996-02-06 Dusa Pharmaceuticals, Inc. Method of applying photodynamic therapy to dermal lesion
EP0704209A1 (en) * 1994-09-20 1996-04-03 JOHNSON & JOHNSON MEDICAL, INC. Transdermally active pharmaceutical composition containing 5-aminolaevulinic acid
US5669916A (en) * 1994-09-28 1997-09-23 The General Hospital Corporation Method of hair removal
US6492420B2 (en) * 1995-03-10 2002-12-10 Photocure As Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy
US7530461B2 (en) * 1995-03-10 2009-05-12 Photocure Asa Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy
EP0820432B1 (en) * 1995-03-10 2001-06-13 PhotoCure ASA Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy
US6992107B1 (en) * 1995-03-10 2006-01-31 Photocure Asa Esters of 5-aminolevulinic acid and their use as photosensitizing compounds in photochemotherapy
WO1997003042A1 (en) * 1995-07-12 1997-01-30 Mitsubishi Chemical Corporation 2,2-dideutero-5-aminolevulinic acid
AU1094597A (en) * 1995-12-01 1997-06-27 Glaxo Group Limited Therapy apparatus and method
GB9608484D0 (en) * 1996-04-25 1996-07-03 Glaxo Group Ltd Flourescent lamp photodynamic therapy (PDT) apparatus and method
SE507490C2 (en) * 1996-08-27 1998-06-15 Medeikonos Ab A method for detecting cancer of the skin of humans and mammals and arrangement for performing the method
DE69729004T2 (en) * 1996-10-10 2005-04-07 The General Hospital Corp., Boston Photodynamic therapy for the treatment of osteosrthritis
GB9700396D0 (en) 1997-01-10 1997-02-26 Photocure As Photochemotherapeutic compositions
US6088612A (en) * 1997-04-04 2000-07-11 Medtech Research Corporation Method and apparatus for reflective glare removal in digital photography useful in cervical cancer detection
US6277067B1 (en) 1997-04-04 2001-08-21 Kerry L. Blair Method and portable colposcope useful in cervical cancer detection
US5989184A (en) * 1997-04-04 1999-11-23 Medtech Research Corporation Apparatus and method for digital photography useful in cervical cancer detection
CA2206203A1 (en) 1997-05-27 1998-11-27 University Of British Columbia Photoactivation of endogenous porphyrins for treatment of psoriasis
DE19744811C2 (en) * 1997-10-02 1999-11-18 Medac Klinische Spezialpraep Use of delta-aminolevulinic acid for the manufacture of a topical medicament for the integral diagnosis and / or therapy of tumors in hollow organs
US6223071B1 (en) 1998-05-01 2001-04-24 Dusa Pharmaceuticals Inc. Illuminator for photodynamic therapy and diagnosis which produces substantially uniform intensity visible light
DE19827417B4 (en) 1998-06-19 2004-10-28 Hahn, Rainer, Dr.Med.Dent. Material for different modification of the optical properties of different cells
WO2000000250A1 (en) * 1998-06-26 2000-01-06 Genetronics, Inc. Synergism of photodynamic and electropermeation effects on cell vitality as a novel cytotoxic agent
US6743222B2 (en) 1999-12-10 2004-06-01 Candela Corporation Method of treating disorders associated with sebaceous follicles
US6190877B1 (en) 1999-12-27 2001-02-20 Edwin L. Adair Method of cancer screening primarily utilizing non-invasive cell collection and fluorescence detection techniques
US6316215B1 (en) 1999-12-27 2001-11-13 Edwin L. Adair Methods of cancer screening utilizing fluorescence detection techniques and selectable imager charge integration periods
DE60307545T2 (en) * 2002-06-21 2007-10-04 Adair, Edwin L., Castle Pines Village Use of metalloporphyrins for the treatment of arteriosclerosis
US6750037B2 (en) 1999-12-27 2004-06-15 Edwin L. Adair Method of cancer screening primarily utilizing non-invasive cell collection, fluorescence detection techniques, and radio tracing detection techniques
US6984498B2 (en) * 1999-12-27 2006-01-10 Adair Edwin L Method of cancer screening primarily utilizing non-invasive cell collection, fluorescence detection techniques, and radio tracing detection techniques
GB0018528D0 (en) * 2000-07-27 2000-09-13 Photocure Asa Compounds
GB0018527D0 (en) * 2000-07-27 2000-09-13 Photocure Asa Composition
AU8541901A (en) * 2000-08-08 2002-02-18 Cytopharm Inc Methods and compositions for treating skin ulcers by topical photodynamic therapy
WO2002013820A1 (en) * 2000-08-11 2002-02-21 Ceramoptec Industries, Inc. Photosensitizing ointment
RU2187347C1 (en) * 2001-01-12 2002-08-20 Государственный научный центр Российской Федерации "НИОПИК" Method and applicator for photodynamic therapy
WO2002089790A1 (en) * 2001-05-03 2002-11-14 Cornell Research Foundation, Inc. Treatment of hpv caused diseases
US6846311B2 (en) * 2002-04-02 2005-01-25 Acueity, Inc. Method and apparatus for in VIVO treatment of mammary ducts by light induced fluorescence
IL148921D0 (en) * 2002-03-26 2002-09-12 Peptor Ltd Photo active backbone cyclized somatostatin analogs for optical imaging and photodynamic therapy
AU2003230808A1 (en) * 2002-04-05 2003-10-27 Candela Corporation High fluence rate activation of photosensitizers for dermatological applications
US20040048842A1 (en) * 2002-09-10 2004-03-11 Mcmillan Kathleen Method of treating skin disorders
US7627363B2 (en) * 2003-03-18 2009-12-01 The General Hospital Corporation Polarized light imaging devices and methods
US7289205B2 (en) * 2003-09-19 2007-10-30 The General Hospital Corporation Fluorescence polarization imaging devices and methods
US20050249669A1 (en) * 2003-10-22 2005-11-10 Academia Sinica Quadruplex stabilizer
US20050209193A1 (en) * 2003-12-05 2005-09-22 Keller Gregory S Method for enhanced photodynamic therapy
US20050267213A1 (en) * 2004-01-08 2005-12-01 Dusa Pharmaceuticals, Inc. Use of photodynamic therapy to enhance treatment with immuno-modulating agents
US20050209330A1 (en) * 2004-03-22 2005-09-22 Syneron Medical Ltd. Method of treatment of skin
US20050209331A1 (en) * 2004-03-22 2005-09-22 Syneron Medical Ltd. Method of treatment of skin
GB0406917D0 (en) 2004-03-26 2004-04-28 Photocure Asa Compounds
US20060052286A1 (en) * 2004-08-13 2006-03-09 Yale University Factor VII conjugates for selectively treating neovascularization disorders
US20060094781A1 (en) * 2004-11-04 2006-05-04 Syneron Medical Ltd. Method of treating extracellular matrix
GB0424833D0 (en) * 2004-11-10 2004-12-15 Photocure Asa Method
US8609073B2 (en) * 2005-03-04 2013-12-17 Dusa Pharmaceuticals, Inc. Compositions and methods for reducing photosensitivity associated with photodynamic therapy
US8021148B2 (en) * 2006-05-03 2011-09-20 Forsyth Dental Infirmary For Children Intraoral light-emitting device
US8246611B2 (en) 2006-06-14 2012-08-21 Candela Corporation Treatment of skin by spatial modulation of thermal heating
GB0700580D0 (en) * 2007-01-11 2007-02-21 Photocure Asa Use
WO2008106966A1 (en) * 2007-03-06 2008-09-12 Christiansen Kaare A method for non-therapeutic or therapeutic photodynamic skin treatment
JP5098051B2 (en) 2007-04-05 2012-12-12 Sbiファーマ株式会社 Mitochondrial disorder brain disease therapeutic agent and diagnostic agent
GB0724279D0 (en) * 2007-12-12 2008-01-23 Photocure Asa Use
WO2009145348A1 (en) * 2008-05-30 2009-12-03 Jfeスチール株式会社 Method for manufacturing pig iron
US20100100083A1 (en) * 2008-10-22 2010-04-22 Scott Lundahl Method of treatment for dermatologic disorders
GB0819594D0 (en) 2008-10-24 2008-12-03 Univ Coimbrra Process
US20100256125A1 (en) * 2009-04-06 2010-10-07 Zila Pharmaceuticals, Inc. Use of improved toluidine blue in photodynamic therapy
JP2010259353A (en) * 2009-05-01 2010-11-18 Sbi Alapromo Co Ltd Method for predicting efficacy of 5-aminolevulinic acid
WO2011009020A2 (en) 2009-07-16 2011-01-20 Mallinckrodt Inc. Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers
CN106908425A (en) 2010-06-21 2017-06-30 思佰益药业股份有限公司 The detection method of urinary tract epidermal carcinoma
EP2713872A4 (en) * 2011-05-26 2014-10-22 3Derm Systems Llc Stereoscopic plug-and-play dermatoscope and web interface
WO2013092936A2 (en) 2011-12-20 2013-06-27 Galderma Research & Development Use of 5-aminolevulinic acid and esters, in combination with a vitamin d derivative or analog in photochemotherapy, and their uses in treating acne
WO2014017046A1 (en) * 2012-07-23 2014-01-30 国立大学法人東京大学 Prophylactic and/or therapeutic agent for radiation damage
US20160287701A1 (en) 2013-12-20 2016-10-06 Galderma Research & Development Pulse photodynamic treatment of photodamaged skin
JPWO2015129535A1 (en) * 2014-02-25 2017-03-30 学校法人産業医科大学 Composition for inducing tumor immunity
CZ307444B6 (en) 2015-04-22 2018-08-29 Jakub Rak Mucoadhesive polymer film for photosensitive therapy in the oral cavity containing photosensitizers
CA3051727A1 (en) 2017-02-06 2018-08-09 3Skin As Sunscreen composition
US10357567B1 (en) 2018-01-12 2019-07-23 Dusa Pharmaceuticals, Inc. Methods for photodynamic therapy

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2208800B2 (en) * 1972-02-24 1977-04-07 A process for producing 5-aminolevulinic acid hydrochloride
US3934369A (en) * 1974-04-23 1976-01-27 University Of Illinois Foundation Vitro net bioxynthesis of chlorophyll and grana
US3973129A (en) * 1975-01-10 1976-08-03 Bell Telephone Laboratories, Incorporated Fluorimetric apparatus and method for analysis of body fluid
EP0048217A1 (en) * 1980-09-12 1982-03-24 Compagnie des Montres Longines, Francillon S.A. Electronic timepiece
JPS5998015A (en) * 1982-11-27 1984-06-06 Microbial Chem Res Found Immunoactivator
EP0330801A1 (en) * 1983-02-08 1989-09-06 Schering Aktiengesellschaft Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease
US4977177A (en) * 1985-04-30 1990-12-11 Nippon Petrochemicals Company, Ltd. Tetrapyrrole polyaminomonocarboxylic acid therapeutic agents
CA1315780C (en) * 1986-01-17 1993-04-06 Yozo Fukuda Porphyrin derivatives
JPS62205081A (en) * 1986-03-03 1987-09-09 Hamari Yakuhin Kogyo Kk Porphyrin derivative
JPH0551613B2 (en) * 1986-05-22 1993-08-03 Seikagaku Kogyo Co Ltd
CA1338764C (en) * 1987-02-03 1996-12-03 David M. Stemerick Polyamine derivatives
US4997639A (en) * 1989-11-27 1991-03-05 Nippon Petrochemicals Company, Limited Method for detecting cholesterol deposited in bodies of mammals

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Br.J.Cancer,Vol.56 No.5(1987) P.589−595
Cancer lett.(Shannon,Irel.),Vol.36 No.1(1987)P.1−10

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US9095165B2 (en) 2008-10-27 2015-08-04 Sbi Pharmaceuticals Co., Ltd. Prophylactic/ameliorating agent for adult diseases comprising 5-aminolevulinic acid, derivative of 5-aminolevulinic acid, or salt of 5-aminolevulinic acid or the derivative of 5-aminolevulinic acid as active ingredient
US9730904B2 (en) 2008-10-27 2017-08-15 Sbi Pharmaceuticals Co., Ltd. Prophylactic/ameliorating agent for adult diseases comprising 5-aminolevulinic acid, derivative of 5-aminolevulinic acid, or salt of 5-aminolevulinic acid or the derivative of 5-aminolevulinic acid as active ingredient
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